Although cirrhosis has long been recognized as an important negative predictor of treatment response for hepatitis C virus (HCV) therapy, the mechanisms underlying this association remain relatively poorly understood. Treatment has progressed rapidly with the introduction of highly effective all-oral therapies, with promising outcomes even in patients with advanced cirrhosis. However, even with the new therapies, it is clear that patients with cirrhosis require special attention. Efficacy continues to be somewhat reduced compared to non-cirrhotic patients and safety is an important concern. In this review, we explore the reasons for treatment non-response in patients with cirrhosis. We focus on how cirrhosis impacts on four important areas including drug delivery, drug uptake and metabolism, immune responses and drug toxicity with examples from the clinical and basic literature. Fortunately, as treatment continues to progress, many of the challenges of treating patients with cirrhosis will become less and less problematic.